Description (Applicant's Description): The major goals of this project are to investigate the sequential changes involved in lung cancer pathogenesis and to determine whether they are useful for risk assessment and as intermediate endpoints for chemoprevention trials. Considerable progress has been made, and 16 manuscripts (9 peer reviewed, 7 invited) have resulted from the work. The major findings include the following: 1) Many clones and subclones of molecular changes have been identified in histologically normal and preneoplastic smoking damaged lung epithelium; 2) the sequential events involved in preneoplasia are being elucidated, and changes are divided into early, intermediate and late; 3) we are determining whether the pattern of changes is predictive of increased cancer risk; 4) extensive allelotyping of lung cancers and cell lines has been performed and the molecular changes in the various forms of lung cancer will be compared; 5) dysregulation of telomerase has been documented during lung cancer pathogenesis, and putative telomerase inhibitors have been identified on chromosomes 3p and 10p; 6) molecular changes in the bronchial biopsies generated as part of the chemoprevention trial (Project 4) are being analyzed. Future work will include: a) mapping the spatial extent and relationships of molecular changes in normal and abnormal bronchial epithelium; b) investigation of the genes involved at several sites of frequent allelic loss on chromosome 4 which were identified during our allelotyping studies; c) identification of the telomerase repressor on chromosome 10p; d) determination of whether molecular changes can be modulated by retinoids.